, Volume 68, Issue 1, pp 105-122
Date: 17 Sep 2012

Parnaparin

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Summary

Abstract

Parnaparin (Fluxum™) is a low molecular weight heparin (LMWH) that is effective and generally well tolerated in the prevention of venous thrombosis, and in the treatment of chronic venous disease and venous and arterial thrombosis. Overall, the efficacy of parnaparin is at least as good as that of unfractionated heparin (UFH), but recent data indicate that parnaparin is more effective in preventing a triple composite endpoint of death, acute myocardial infarction (MI) and myocardial revascularisation in patients with unstable angina or acute ST-segment elevation myocardial infarction (STEMI). As with other LMWHs, parnaparin has a more convenient, once-daily, subcutaneous administration regimen and better local tolerability than UFH. Very little evidence comparing LMWHs is available but, because of similarities between these agents, very large studies would be needed to show significant differences. Meanwhile, data indicate that parnaparin is a useful option in the range of available LMWHs.

Pharmacological Properties

Parnaparin has a mean molecular weight of about 4.5 kDa. Following administration of parnaparin, dose-dependent effects were evident with all pharmacodynamic parameters, but factor Xa was markedly inhibited for many hours, whereas the effect on factor IIa (thrombin) and activated partial thromboplastin time (aPTT) was less evident and transient. Furthermore, parnaparin has a higher ratio of anti-Xa to anti-IIa activity than UFH.

In vitro, parnaparin appeared to have a more potent effect than UFH and enoxaparin in modifying platelet-polymorphonuclear leukocyte function, thus reducing their potential prothrombotic role. Parnaparin retained greater anticoagulant activity than UFH in the presence of activated platelets. Bleeding times were not affected with doses of subcutaneous parnaparin ≤12 800 IUaXa in healthy volunteers. In patients with suspected acute MI, parnaparin decreased fibrin formation in a dose-dependent manner.

Parnaparin is rapidly absorbed and its maximal anti-Xa activity is reached within about 3 hours of subcutaneous administration, regardless of dose. The bioavailability of the drug is almost 100% and is not affected by the site of injection. Following repeated once-daily subcutaneous administration, steady-state inhibition of factor Xa activity is achieved within 2–4 days and there is no evidence of drug accumulation. As with other LMWHs, parnaparin is eliminated renally. Plasma clearance was not affected by dose, but the plasma elimination half-life increased dose dependently.

Therapeutic Efficacy

Subcutaneous parnaparin 3200–6400 IUaXa once daily was at least as effective as subcutaneous UFH 5000 IU two or three times daily, both usually administered for 7 days, in preventing deep vein thrombosis and pulmonary embolism in clinical trials of patients undergoing major surgery.

Medium-term (up to 3 months) treatment with subcutaneous parnaparin significantly improved venous haemodynamics, including venous pressure, and clinical symptoms, including oedema and pain, from baseline to a similar extent to that demonstrated with subcutaneous UFH 12 500–15 000 IU/day in trials of patients with chronic venous insufficiency and phlebopathies.

Subcutaneous parnaparin 6400 IUaXa once daily for 7 days was associated with a significantly lower incidence of a triple composite endpoint of death, acute MI or the need for myocardial revascularisations than UFH given intravenously for 48 hours, then subcutaneously (UFH 5000 IU every 6 hours) for 5 days (7% vs 11%; p = 0.034) in a randomized, multicentre study in patients (n = 897) with unstable angina.

Similarly, in patients with an acute STEMI, subcutaneous parnaparin 4250 IUaXa every 12 hours for 7 days was associated with a lower incidence of a triple composite endpoint of death, acute MI or the need for myocardial revascularization in the 45 days following the start of treatment than intravenous UFH administered for 3 days followed by subcutaneous UFH 7500 IU every 12 hours for 4 days (27% vs 42%; p = 0.03).

In patients with stable angina, parnaparin 6400 IUaXa once daily, together with conventional therapy, significantly increased exercise time compared with placebo.

Long-term treatment (6–8 months) with subcutaneous parnaparin 6400 IUaXa once daily significantly improved pain-free walking time/distance compared with baseline in several studies of patients with peripheral arterial obstructive disease. The extent of improvement with parnaparin was similar to that demonstrated with UFH in one study.

Tolerability

Subcutaneous parnaparin is generally well tolerated. Compared with UFH, parnaparin 3200 or 6400 IUaXa once daily was associated with a significantly lower incidence of minor bleeding in patients with unstable angina and a numerically lower incidence of minor bleeding in postsurgical patients. The incidence of major perioperative bleeding events was low in recipients of parnaparin with acute STEMI or those undergoing surgery and not significantly different to that reported with UFH. Compared with UFH, parnaparin has a reduced effect on platelet count and aPTT.

Routine laboratory parameters were generally not significantly affected by therapeutic dosages of parnaparin. Heparin-induced thrombocytopenia has not been reported in clinical trials of parnaparin.

Various sections of the manuscript reviewed by: G. Boriani, Institute of Cardiology, University of Bologna, Bologna, Italy; C. Cerletti, Center for High Technology Research and Education in Biomedical Sciences, Catholic University, Campobasso, Italy; J. Fareed, Hemostasis & Thrombosis Research Laboratories, Loyola University Medical Center, Chicago, Illinois, USA; N. Maugeri, Center for High Technology Research and Education in Biomedical Sciences, Catholic University, Campobasso, Italy; G. Melandri, Institute of Cardiology, University of Bologna, Bologna, Italy; H.L. Messmore, Hines Veteran’s Affairs Hospital, Hines, Illinois, USA; R. Pesavento, Department of Medical and Surgical Sciences, University of Padua, Padua, Italy; P. Prandoni, Department of Medical and Surgical Sciences, University of Padua, Padua, Italy; R. Verhaeghe, Department of Molecular and Cellular Medicine, University of Leuven, Leuven, Belgium.

Data Selection

Sources: Medical literature published in any language since 1980 on ‘parnaparin’, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Wolters Kluwer Health | Adis). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.
Search strategy: MEDLINE, EMBASE or AdisBase search terms were ‘parnaparin’ or ‘parnaparin sodium’. Searches were last updated 12 December 2007.
Selection: Studies in patients who received parnaparin. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.
Index terms: Parnaparin, acute coronary syndromes, heparin, low molecular weight heparin, pharmacodynamics, pharmacokinetics, therapeutic use, venous thromboembolism, tolerability.